The present invention relates to the surgical management of cancer patients and more particularly to a technique for determining, i.e., detecting and differentiating, neoplastic tissue or tumors in cancer patients utilizing somatostatin congeners.
Endogenously produced somatostatin exerts tonic inhibition on release of several pituitary peptides including growth hormone, adrenocorticotropin hormone, prolactin, and thyroid stimulating hormone. Prolactin has mitogenic properties in both endocrine cells and normal lymphocytes; thus, somatostatin or its congeners may exert antiproliferative effects on any endocrine tumor which is stimulated by prolactin, such as breast and prostate cancers. Somatostatin also inhibits release of several intestinal peptides such as insulin, glucagon, motilin, gastric inhibitory peptide (GIP), vasoactive intestinal peptide (VIP), secretin, cholecystokinin, bombesin, and gastrin releasing peptide (GRP). This latter peptide stimulates proliferation of normal and malignant intestinal epithelial cells. GRP also stimulates the proliferation of normal bronchial epithelial cells and is an autocrine growth factor in small cell lung carcinoma.
Two principal molecular forms of somatostatin are known: somatostatin-14 (S-14) and somatostatin-28 (S-28). The structural differences appear to influence the relative degree of inhibitory activity that these molecules exert on the biologic functions which they regulate. S-14 is a 14-amino acid peptide with a cyclic molecular structure stabilized by a disulfide bond between cysteine residues (positions 3 and 14 from the amino-terminal group) and by hydrogen and hydrophobic bond. The amino acid sequence of S-14 is strikingly constant among vertebrate species, including man: (H)-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-(OH). S-28 is a 28-amino acid peptide that contains the same amino acid sequence as S14, but has 14 additional amino acids attached to the amino-terminal end.
Studies of structure-activity relationships among a variety of synthetic somatostatin-like peptides have revealed that the biologic activity of somatostatin resides primarily in four amino acids within the ring structure: Phe.sub.7 -Trp-Lys-Thr.sub.10. By eliminating amino acids that are not required for biologic activity and adding non-biologic D-amino acids to reduce enzymatic degradation, chemists have produced a variety of somatostatin-like-peptides that are more potent and longer acting than native somatostatin. For example, octreotide acetate, a synthetic somatostatin analogue, is 45 to 70 times more potent than native somatostatin in inhibiting growth hormone release. Octreotide acetate contains only eight amino acids in the following sequence: D-Phe-Cys-Phe.sub.3 -D-Trp-Lys-Thr-Cys-Thr-(ol). lanerotide, also a synthetic somatostatin analogue and an octapeptide, is 20 to 50 times more potent than native somatostatin. It is similar to octreotide but bears a D-.beta.-naphthylalanine in the first position and a valine in the sixth position, and has been tyrosinated in the third position.
Somatostatin receptors have been identified in endocrine and non-endocrine human tumors using audioradiographic techniques (e.g., adenomas, meningiomas, mediastinal carcinoid tumors, intestinal carcinoma, and mammary carcinomas). Biochemical characterization of somatostatin binding to cell membranes prepared from human meningiomas and pituitary adenomas has revealed specific, high-affinity somatostatin receptors. Somatostatin receptors in human pituitary adenomas are comparable to somatostatin receptors in normal rat pituitary tissue with respect to their binding characteristics, although human adenomas have higher receptor densities. The presence of somatostatin receptors in tumor tissues may be of clinical interest if such receptors can be linked to the anti-proliferative properties of somatostatin.
Somatostatin and octreotide acetate, the aforementioned synthetic analogue, are ringed structures which do not contain a tyrosine moiety. The addition of tyrosine enables such compounds to be radiolabeled by means of a standard chloramine-T iodination procedure, utilizing, for example, either .sup.1231 I or .sup.1251 I. Tyrosinated forms of native somatostatin (bearing a tyrosine moiety at either the 1 or 11 position) have been shown to be impractical since they are susceptible to enzyme degradation. However, it has been found that various tyrosinated analogues of somatostatin are resistant to circulating and membrane enzyme degradation and can be exploited for radioiodination use. One such analogue is tyrosinated octreotide acetate. Octreotide acetate (which is referred to variously in the literature as Sandostatin.RTM. or SMS 201-995 or simply octreotide) is tyrosinated at the 3 position and thus referred to as Tyr.sup.3 -octreotide: D-Phe-Cys-Tyr.sub.3 -D-Trp-Lys-Thr-Cys-Thr-(ol). A second tyrosinated compound which is preferred for use in accordance with the present invention is lanresotide (also known as Somatuline.RTM. or BIM 23014), an octapeptide having the following amino acid sequence: D-.beta.-Nal-Cys-Tyr.sub.3 -D-Trp-Lys-Val-Cys-Thr-(NH.sub.2).
Further information can be found by reading O'Dorisio et al., "Somatostatin and Somatostatin-like Peptides: Clinical Research and Clinical Applications", Advances in Endocrinology and Metabolism, vol. 1, pp. 1.75-230, Mazzaferri et al., eds. (Mosby Year Book, 1990); O'Dorisio et al., "Rationale for Somatostatin Therapy and its Clinical Application as the Congener, Octreotide Acetate", Endocrine Cancer, Mazzaferri et al., eds. (to be published); Harris, "Future Medical Prospects for Sandostatin, Metabolism, vol. 39, no. 9, suppl. 2 (September) 1990, pp. 180-185; Lamberts et al., "Treatment with Sandostatin and In Vivo Localization of Tumors with Radiolabeled Somatostatin Analogs", Ibid at pp. 152-155; Bakker et al, "Receptor Scintigraphy with a Radioiodinated Somatostatin Analogue: Radiolabeling, Purification, Biologic Activity, and In Vivo Application in Animals", J. Nucl. Med., 1990, 31: 1501-1509; Lamberts et al., "Somatostatin Receptor Imaging In Vivo Localization of Tumors with a Radiolabeled Somatostatin Analog", J. Steroid Biochem. Molec. Biol., vol. 37, no. 6, pp. 1079-1082 (1990); Reubi et al., "In Vitro and in Vivo Detection of Somatostatin Receptors in Pheochromocytomas and Paragangliomas", J. Clin. Endocrinol. Metab., vol. 74, pp. 1082-1089 (1992); Krenning et al., "Somatostatin Receptor Imaging of Endocrine Gastrointestinal Tumors", Schwiez. med. Wschr., 1992, 122: 634-637; Reubi et al., "Somatostatin Receptor Incidence and Distribution in Breast Cancer Using Receptor Autoradiography: Relationship to EGF Receptors", Int. J. Cancer, 46, 416-420 (1990); Pantev et at., "Evaluation of Somatostatin Receptors in Human Cancer", Wien Klin Wochenschr, (1991) 103/21: 649-653; Lemaire et al., "Disposition of Sandostatin, a New Synthetic Somatostatin Analogue, in Rats", Drug Metabolism and Disposition, vol. 17, no. 6, pp. 699-703 (1989); Kwekkeboom et at., "Radioiodinated Somatostatin Analog Scintigraphy in Small-Cell Lung Cancer", J. Nucl. Med., 1991, 32: 1845-1848; Krenning et at., "Somatostatin Receptor Scintigraphy with Indium-111-DTPA-D-Phe-1-Octreotide in Man: Metabolism, Dosimetry and Comparison with Iodine-123-Tyr-3-Octreotide", J. Nucl. Med., 1992, 33: 652-658; Lamberts et al., "The Role of Somatostatin and Its Analogs in the Diagnosis and Treatment of Tumors", Endocrine Reviews, vol. 12, no. 4, pp. 450-482 (1991); B altershill et al., "Octreotide: A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Conditions Associated with Excess Peptide Secretion", Drugs, 38 (5), 658-702 (1989); Katz et al., "Octreotide, A New Somatostatin Analogue", Clinical Pharmacy, vol. 8, Apr. 1989, pp. 255-273; Lamberts, "A Guide to the Clinical Use of the Somatostatin Analogue SMS 201-995 (Sandostatin)", Acta Endocrinologica (Copenh), 1987, suppl. 286, pp. 54-66; and Evers et al., "Somatostatin and Analogues in the Treatment of Cancer", Annals of Surgery, Mar. 91 213 (3), pp. 190-198, the disclosures of all of the foregoing being expressly incorporated herein by reference.